�Rational use of Antibiotic & Principles of Antimicrobial Chemotherapy�

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Dr Bassi

Overview : �

• Define Rationale & Irrational use of antibiotics
• Consequences of inappropriate use of antibiotics
• Determinants of irrational use of antibiotics
• General principles
• Basic principles of pharmacokinetics & pharmacodynamics
• Types of antibiotics
• Drug selection
• Avoiding inappropriate use to minimize resistance

What is Rational Use of Drugs?

• Rational Use of Drugs

Requires that patients receive medicines appropriate to their

clinical needs, in doses to meet individual requirements, for an

adequate period of time, at the lowest cost to them. (WHO 1988)

• Correct Drug; Correct Dose; Correct Duration !!!

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��What is irrational use of antibiotics (IUA)

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• IUA is define as use of wrong antibiotics, in wrong dose, by wrong route of administration, for wrong interval and duration and in wrong dosage form…

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Determinants of irrational use of antibiotics

• Physician related

- Lack of knowledge

- Delayed lab results,

- Fear of clinical failure

- Inappropriate peer norms,

- Local medical culture

- Economic incentives

-Patient demand of “ quick fix”

•  Pharmacist/dispenser related

- Economic incentives

- Lack of regulations and enforcements

- Unclear role as health providers

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Determinants of irrational use of antibiotics

• On the part of patients

- Lack of access to proper health care

- Beliefs and traditions

- Marketing pressures

- Economic considerations

• On the part of policymakers, regulators and pharmaceutical industry

- Lack of rational drug policy , regulations

- Uncontrolled marketing tactics

- Lack of infrastructure

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4 Es of IUA

• 4 Es of IUA

E ducation

- Suboptimal approach to diagnosis and Rx.

- Lack of knowledge of natural course of viral diseases.

E xperience

- Diagnostic and prescribing habits of doctors.

E xpectations

- Belief that patient expects antibiotics.

E conomics

- Time pressures, need to return to work.

• Consequences of IUA: Antimicrobial resistance, Adverse Drug Reactions, Increased cost burden.

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�Using antibiotics the right way : �

• Most commonly prescribed
• Most commonly misused

- Treatment failure

- Increased cost

- Prolonged holding times

- Poor reputation Development of antimicrobial resistance

• Adverse effects do occur
• Lack of overt problems or complications does not mean they don’t happen!

- In our patients

- In the population

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The Basic Concepts

• Pharmacokinetics : what the body does to a drug
• Pharmacodynamics : what the drug does to a body
• Cmax - Maximum Plasma Drug Concentration
• AUC - Area Under the Curve
• Minimum Inhibitory Concentration (MIC ): Minimum Inhibitory Concentration Determined by serial tube dilutions - lowest concentration of drug that prevents visible growth of an isolate
• Important :

- MIC is specific to that particular bacterial isolate and that particular drug

- Cmax or some multiple thereof must be maintained at or above the MIC for some portion of the day

- Some drugs also have a post-antibiotic effect

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• “It can’t hurt and it might help” should not be the reason you are prescribing antibiotics!

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General principles

1. Use appropriate antibiotic therapy :

• Perception of need - Is an antibiotic necessary?
• Choice of antibiotic - What is the most appropriate antibiotic?
• Choice of regimen - What dose, route, frequency and duration are needed?
• Monitoring efficacy - Is the treatment effective?

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Categorizing Antibiotics : �

2. Categorize based on PK/PD parameters rather than bacteriostatic and bactericidal classifications:

• Time-dependent antibiotics – beta lactams, macrolides, lincosamides

- Most important parameter: t > MIC

- Maintain drug concentration above MIC most of the time

• Conc.-dependent antibiotics – fluoroquinolones, aminoglycosides, metronidazole

- Most important parameter: Cmax:MIC ratio or AUC:MIC ratio -

- Achieve higher plasma drug concentrations �

General principles

3.Clinical assessment

- Type of patient

- Likely infecting organism

General principles: �

4. Host factors:

A,Age; Some drugs are contraindicated in children

Tetracycline, because they may discolor the teeth. Quinolones are used with precaution because of concerns over arthropathy . Renal function and creatinine clearance reduced in elderly, doses need to be reduced.

B, Renal and hepatic function: Alters the pharmacokinetics of the drugs

• Aminoglycosides and glycopeptides need to be used very carefully even in mild renal failure.
• Beta lactams precipitates seizures in renal impairment.
• Macrolides , cloramphenicol , metronidazole , rifampicin and isoniazid ; doses need to be reduced in liver failure.

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C,Pregnancy;

• Aminoglycosides and tetracyclines should be avoided Penicillins , cephalosporins and macrolides appear to be safe.
• Drugs like trimethoprim , metronidazole and macrolides enter breast milk.

D,Site of infection;

• Antibiotics need to achieve sufficient local concentration at the infected site for effective microbial killing to occur
• Abscesses will require drainage,
• necrotic material to me debrided

E,Immune status

- AIDS, hematological malignancies ; influence both the likelihood of an infection and its likely etiology.

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General principles: �

General principles: �

F,Presence of prosthetic material ;

- Rarely respond to antibiotic therapy

- Usually require removal of device

G,Allergy

- Determination of previous allergic drug reactions, including antimicrobial agents.

- Failure to do so can have catastrophic consequences

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General principles: �

B) Likely infecting agent: �

• Clinical assessment may allow
• a likely source of infection.
• Empirical treatment is aimed at these organisms..
• Laboratory investigations supports to establish a definitive microbiological diagnosis.

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General principles

5.Other considerations

A, Routes of administration:

• Parenteral therapy: Seriously ill patient, where effective drug concentrations are required rapidly at the site of infection. Drugs not orally absorbed e.g. aminoglycosides , glycopeptides Oral route is contraindicated Patient usually switched to oral formulation after 48-72 hours.
• Oral therapy
• Topical : Superficial skin infections, mucosal candidiasis , middle ear and superficial ocular infections

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General principles: �

B, Dosage regimens

- Dose influenced by severity of infection, age and weight of the patient.

- Standard treatment guidelines should be followed.

C, Encouraging compliance

- Less frequency improves compliance

D, Length of treatment

- Depends upon site and severity of infections, causative organisms and patients response to the treatment.

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General principles

E, Combination therapy: �A, - High risk of toxicity, interactions

B, - High cost, Less compliance

C, - Useful in empirical therapy to cover several pathogens, e.g. Severe community acquired pneumonia ; combination of beta lactam and macrolide is used and in Brain abscesses ; ceftriaxone + metronidazole

D, -Treatment of mixed infections - E.g. intra-abdominal infections Gram negative agent ( Ceftriaxone / aminoglycoside ) + Metronidazole (broad spectrum anaerobic) + Amoxycillin (against enterococci )

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General principles: �

E, Combination therapy Synergy : E.g. beta lactams + Aminoglycosides more effective than penicillin alone in streptococcal endocarditis .

F, Broadening of antimicrobial activity : Combination of antibiotic + Enzyme inhibitor e.g. amoxicillin + clavulanic acid, and inhibitors against human enzymes, to reduce metabolism of antibiotics. E.g imipenam + cilastin .

G,Avoiding drug resistance : E.g. quadruple therapy for tuberculosis

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Antibiotic Selection : �

• First things first!
• Is there an indication for antibiotic therapy in this patient?

- Delay appropriate treatment

- Avoid waste of resources

- Think about development of resistance

• Yes we need antibiotics. where is the infection?

Make an educated guess on type of bacteria present

- May influence drug selection (Prostate, eye, CNS)

- May influence duration of treatment

- Guides sample collection

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Antibiotic Selection

• I know where the infection is!

- What bacteria is most likely to be found in that location?

- Sample collection for culture & sensitivity

- or cytologic evaluation

• I know what bacteria is likely to be causing the problem. What antibiotics is most likely to be effective against this bacteria?

- Based on historical sensitivity data

- Becoming less and less reliable

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Antibiotic Selection

• Any factors that might affect this?

- Previous antibiotic therapy

- Volume of distribution, local factors

• By what route do I want to give this antibiotic?
• What dose and for how long?

- Dictated by patient & drug Compliance,

- convenience,

-cost

• Some guesswork involved .Any factors that might affect this?

- Acute vs. chronic infections

- Immunosuppression

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�The Use of Culture & Sensitivity Testing �

• Ideal for guiding appropriate therapy

- Better for picking which drugs NOT to use

- BUT – of limited practicality

- Expense ,- Turnaround time, - Inherent limitations, Isolated

organisms and In vitro results

Consideration for:

- Particularly unusual case

- Treatment failures

- Population-level problems

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Interpreting Sensitivity Results

• Compare MIC of that isolate to breakpoint MIC for that drug
• Breakpoint MIC = highest drug concentration likely to be achieved in a patient with recommended dosing

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Using Sensitivity Results

• One drug may be considered representative of that category Not necessarily true!
• In general

- avoid drugs with resistant or intermediate designations

* More likely to promote resistance

* More likely to have treatment failures

*Exceptions exist

• Select drugs designated as susceptible.

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Using Sensitivity Results

• Consider: MIC furthest away from the breakpoint MIC

Narrow-spectrum

Compliance with dosing regimen

Ability to give multiple doses a day

Safety of higher doses

Margin of safety

Cost effective

• Cytologic evaluation :

Don’t underestimate the value of cytology!

Morphology

Gram stain

Type of inflammatory cells

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Empirical selection of antibiotics �

• Empiric selection of antibiotics Is the selection of an antibiotic without identifying the causative organism & its susceptibility pattern

- Essentially playing the odds using your best guesses

- Most likely pathogens

- Historical susceptibilities

- Works better in some cases than others

• Makes selecting the appropriate antimicrobial and dose for the most probable pathogen at each location a simpler process
• Ranks the efficacy of 24 antimicrobials against 13 of the most common pathogens
• Select the most cost-effective antimicrobial and dosage for maximum efficacy
• Formulary section

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Prophylactic Antibiotics for Surgery �

• Prophylactic Antibiotics will not make up for poor surgical technique!
• Prevent bacterial infection as a result of potential contamination
• If they will be effective, they must be:

- effective against the likely contaminants

- present at the site at the time of contamination

• Some degree of contamination is likely but infection is unlikely

- Degree of contamination

- Virulence of the bacteria

- Strength of host defenses

- Tissue health and integrity

• Post-op infection risk factors: Prolonged duration of surgery/anesthesia Traumatic tissue handling Lack of aseptic technique, dirty surgical field Multiple people in sx suite

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Prophylactic antibiotics will not make up for poor

surgical technique. They are not a substitute for

aseptic technique, gentle tissue handling, and short

anesthetic and surgical times.

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Antimicrobial Resistance �

• Biggest unseen problem relating to antibiotic usage

- Both human and animal health

- Eventually impacts individual patient care

• Take appropriate steps to minimize development of resistance
• Key point

selection pressure for resistant organisms to survive and replicate

Risk factors for resistance

- previous antibiotic treatment

- Inappropriately low dose

- Prolonged period of time

Inherent vs. Acquired Mycoplasma & beta lactams MDR Salmonella spp.

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Acquired Resistance

• Bacteria have different mechanisms

- Enzymes to destroy the drug

- Efflux pumps

- Modification of target site

-Change in porin size or number

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Development of Resistance �

• Common to have >1 type of resistance

- Can be transmitted rapidly

- Many mechanisms not specific to drug class

- May lead to development of MDR strains of numerous species (GI normal flora)

• Chromosomal mutations

- “First-step” mutations usually cause low-level resistance

- Multiple mutations can cause greater resistance

• Bacteria may get a competitive advantage
• Plasmid transmission
• Extra chromosomal pieces of DNA
• Occurs within & across species
• Requires only a single event – rapid and complete

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Avoiding Resistance �

• Only use antibiotics when a bacterial infection exists!
• Choose as narrow-spectrum a drug as possible
• Select a dose the will ensure adequate drug concentrations at the site of infection

- High enough to prevent “first-step” mutations

- Maintain t > - - MIC at 70% or greater

- Cmax:MIC ratio > 8-10,

- AUC:MIC ratio 125-250

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Treat the infection right the first time –

• the right drug,
• at the right dose,
• for the right amount of time.

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Dead bugs don’t mutate!

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Optimizing Antibiotic Therapy �

• Give an appropriate dose that will kill the bacteria and minimize the development of resistance

- t > MIC for at least 60-70% of the dosing interval

More frequent dosing

+/- higher doses to add a half-life

Cmax:MIC of 8-10 or a AUC:MIC > 100-125

Higher doses +/- more frequent doses to increase AUC

•  Bacteriostatic vs. bactericidal levels
• Oral vs. parenteral administration
• Remember – need adequate drug concentrations at the site of infection

Capillary tight junctions

Poor blood supply

Intracellular infections

Inflammatory cells and debris

Optimizing Antibiotic Therapy �

• Hemodynamic changes

- Dehydration, - shock, - fluid therapy

• Renal or hepatic disease
• Age? Older – may have a higher percentage of body fat

Neonates - higher percentage of body water, decreased drug protein binding

• Consider combination therapy

Improve the spectrum of activity Helpful or even necessary with polymicrobial infections Shorter duration of treatment may be possible Reduced risk of adverse drug reactions

• Synergistic combinations – drugs work on different targets or through sequential pathways Beta lactam & fluoroquinolone Beta lactam & aminoglycoside

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�Optimizing Antibiotic Therapy �

• Avoid antagonist combinations: Chloramphenicol & erythromycin . Tetracycline & fluoroquinolones
•   Remember: Antibiotic + patient ? = Cure

If you don’t take all the factors into consideration

Host factors

Drug factors Bacterial factors

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What we can do ? �

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To improved Rational Use of Antibiotics

1.Educating Practitioners:

Seminars, Panel discussion, Updates Educating Practitioners

 Let the advertisements not block your intelligence! * Reading the fine print!

1. The drug is 10 times more potent: But may cause renal damage in some

2. The most effective antibiotic: For what? , At what cost? Or What duration?

3. Educating Consumers: No own antibiotic kit , No self medication, Emphasis on dose and duration

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Guidelines

• Essential drug list: Essential drugs are those that satisfy the needs of the majority of the population. They should therefore be available at all times, in adequate amounts, and in the appropriate dosage forms.
• Standard Treatment Guidelines: A systematically developed statement to assist practitioners in making decisions about appropriate health care for specific clinical conditions These guidelines should be tailored to the local situations and specific to levels of care From national level to hospital level.

  Key features of STGs: Is Simplicity, Credibility Same standard for all levels Drug supply based on STG’s Introduce in pre-service training (Internship/House job), Dynamic (regular updates), Handy pocket books 

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Surveillance

• Surveillance : Two complementary types of surveillance are recommended Surveillance for antibiotic resistance Surveillance for antibiotic use Knowing resistance levels and tracking them over a period of time is a powerful tool to support real changes. Once the link between resistance and antibiotic is accepted, tracking antibiotic use can be used as a surrogate for changes in antibiotic resistance.
• Increasing the use of diagnostic tests: �Increasing the use of diagnostic tests Lack of adequate, well equipped laboratory facilities. Under-utilization of microbiological labs. Ministry of Health & Family Welfare recommends for increase in the utilization of diagnostic tests in the clinical practice.

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Antibiotic policy �

• Antibiotic policy A corporate document that is designed to further the aim of the hospital to provide a high standard of patient care. The principles of antibiotic policy were laid down in the 1980s.
• Objectives of the Antibiotic Policy: To provide the most effective and empirical treatment for individual patient with minimal adverse reactions. To motivate the rational use of antibiotics To prevent the development of drug resistance by judicious and timely use of relevant antibiotics. Cost effective and rational use of drugs for treatment.

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Antimicrobial Management Team �

• Antimicrobial Management Team To design and implement antibiotic policy. Composition Infectious disease physician (Member secretary) Infection control officer- a senior microbiologist. Clinical microbiologist Surgeon Clinical pharmacologist Clinical pharmacist
• Antimicrobial Management Team: Functions- Providing high standard of patient care Improving rational utilization of antibiotic. Pharmacovigilance of antimicrobial Effective utilization of financial resources in purchase of antimicrobials Curbing emergence of microbial resistance.

�Antibiotic policy ��

• Antibiotic policy Educational programs designed to improve antibiotic uses. Controls operated through the Pharmacy department. Creation of hospital pharmacopeia. Written justification for the costlier and broader spectrum of antibiotics. Introduction of concept of stop orders Sponsoring of antibiotics according to their usage e.g. prophylaxis, specific therapy, therapeutic trials etc.
• Antibiotic policy Controls through the laboratory in the form of reporting, regular issue of resistance/susceptibility patterns and active consultations. Establishment of an antibiotic advisory service in the hospital. Publication of consensual antibiotic policy for special use e.g. prophylaxis and specialized clinical units.
• Antibiotic policy Audit of antibiotic usage; antibiotics as a class of drugs accounts for the largest expenditure in health care system. Promotion of ethical relationship between the pharmaceutical companies, prescribers and pharmacists.
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�Summary ��

• Summary Infectious diseases are still a serious problem, compounded by the development of antibiotic resistance in many bacteria and the relative lack of newer antimicrobial agents to combat these multi-resistant organisms.
• Appropriate aggressive short-course treatment is recommended for ensuring clinical and microbiologic cure, optimal patient adherence, and minimal generation of antibiotic resistance..

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Final Thought

“ The desire to take medicines is one feature which distinguishes man, the animal from his fellow creatures. It is one of the most serious difficulties with which we have to contend ”

- Sir William Osler (1894)

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Thank you